Is CFHR3 p.Leu282Phe (c.846A>T) pathogenic?

CFHR3 p.Leu282Phe (c.846A>T) is classified Uncertain significance in CFHR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-14). AlphaMissense: likely benign (0.2327); Absent from gnomAD v4.1.

How common is CFHR3 p.Leu282Phe (c.846A>T) in the general population?

CFHR3 p.Leu282Phe (c.846A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CFHR3 p.Leu282Phe (c.846A>T)?

AlphaMissense predicts likely benign (score 0.2327) — an in-silico prediction, not a clinical call.

CFHR3 p.Leu282Phe

c.846A>T · VCV4001750

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2327 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2327	likely benign
REVEL	0.336	indeterminate
SaProt	LLR -7.51	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.6	GERP -3.6
Regional constraint	o/e 0.95	unconstrained · MANE · 3,283 bp · p 0.67 · regional, not allelic
Overall
CADD	1.088	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CFHR3
Protein: p.Leu282Phe
Coding: c.846A>T
MANE Select: NM_021023
Type: single nucleotide variant
Location: chr1:196793366 (GRCh38)
Gene constraint: LOEUF 1.302 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.93
Residue 282: a disulfide bond; the sushi 5 domain

Full CFHR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFHR3 p.Leu282Val Uncertain significance ★ ⚠ same residue
CFHR3 c.796+1G>A Uncertain significance ★★ same type
CFHR3 p.Arg320Gln Uncertain significance ★★ ⚠ same type
CFHR3 p.Gly119Ala Uncertain significance ★★ ⚠ same type
CFHR3 p.Ile70Thr Uncertain significance ★★ ⚠ same type
CFHR3 p.Tyr118Ter Uncertain significance ★★ same type
CFHR3 c.431-88C>T Benign ★★ same type
CFHR3 c.58+8A>G Likely benign ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cfhr3-p-leu282phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown